WO2022061202A1 - Compositions et méthodes pour traiter le cancer - Google Patents

Compositions et méthodes pour traiter le cancer Download PDF

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WO2022061202A1
WO2022061202A1 PCT/US2021/051024 US2021051024W WO2022061202A1 WO 2022061202 A1 WO2022061202 A1 WO 2022061202A1 US 2021051024 W US2021051024 W US 2021051024W WO 2022061202 A1 WO2022061202 A1 WO 2022061202A1
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cancer
compound
inhibitors
subject
pharmaceutically acceptable
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PCT/US2021/051024
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English (en)
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Jean-Michel Vernier
David A. Nathanson
Michael E. Jung
Timothy F. CLOUGHESY
Lorenz URNER
Peter M. Clark
Jonathan Tsang
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The Regents Of The University Of California
Erasca, Inc.
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Priority to US18/027,313 priority Critical patent/US20240058340A1/en
Publication of WO2022061202A1 publication Critical patent/WO2022061202A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/66—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving blood sugars, e.g. galactose
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis

Definitions

  • EGFR epidermal growth factor receptor
  • GBM glioblastoma
  • oncogenic signaling drives glucose metabolism to suppress intrinsic apoptosis and promote survival.
  • Inhibition of oncogenic drivers with targeted therapies can trigger the intrinsic apoptotic machinery as a direct consequence of attenuated glucose consumption.
  • the intertwined nature of these tumorigenic pathways may present therapeutic opportunities for rational combination treatments, however, this has yet to be investigated.
  • brain penetrant chemotherapeutics for the treatment of glioblastoma and other cancers.
  • the present disclosure provides compounds having a structure represented by Formula I: wherein: R 1 is selected from the group consisting of R 2 is selected from C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl, each of which is optionally substituted with one or more halogen, or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides methods of inhibiting EGFR or ⁇ EGFR, comprising administering to a subject an amount of a compound of the disclosure.
  • the present disclosure provides methods of treating cancer comprising administering to a subject in need of a treatment for cancer an amount of a compound of the disclosure.
  • the cancer is glioblastoma multiforme.
  • the present disclosure provides methods of treating cancer comprising administering to a subject a glucose metabolism inhibitor and a cytoplasmic p53 stabilizer, wherein the glucose metabolism inhibitor is a compound of the disclosure.
  • the cancer is glioblastoma multiforme.
  • FIG.1A shows the enantiomeric purity of synthetic intermediate 5 as determined by chiral SFC (Chiralpak AD-3 column, 40% MeOH).
  • FIG.1B shows the enantiomeric purity of synthetic intermediate (S)-5 as determined by chiral SFC (Chiralpak AD-3 column, 40% MeOH).
  • FIG.1C shows the enantiomeric purity of synthetic intermediate (R)-5 as determined by chiral SFC (Chiralpak AD-3 column, 40% MeOH).
  • FIG.1D shows the disastereomeric purity of Mosher ester derivatives 5 as determined by chiral SFC (Chiralpak AD-3 column, 40% MeOH).
  • FIG.2 depicts the activities of erlotinib, lapatinib, gefitinib, and exemplary compounds of the disclosure against U87 EGFRwt.
  • FIG.3 depicts the activities of erlotinib, lapatinib, gefitinib, and exemplary compounds of the disclosure against U87 EGFRvIII.
  • FIG.4 depicts the activities of erlotinib, lapatinib, gefitinib, and exemplary compounds of the disclosure against HK301, a patient derived, EGFRvIII mutant GBM gliomasphere.
  • FIG.5 depicts the activities of erlotinib, lapatinib, gefitinib, and exemplary compounds of the disclosure against GBM39, a patient derived, EGFRvIII mutant GBM gliomasphere.
  • FIG.6 depicts the activities of erlotinib, lapatinib, and exemplary compounds of the disclosure in a GBM39 EGFRvIII mutant mouse model.
  • FIG.7A depicts the activities of erlotinib and exemplary compounds of the disclosure in a HCC827 lung cancer EGFR mutant cell line.
  • FIG.7B depicts the activities of erlotinib and exemplary compounds of the disclosure in a PC9 lung cancer EGFR mutant cell line.
  • FIG.7C depicts the activities of erlotinib and exemplary compounds of the disclosure in a H838 lung cancer mutant cell line.
  • FIG.8 depicts the activities of erlotinib and exemplary compounds of the disclosure in a PC9 lung cancer EGFR mutant mouse model.
  • FIG.9 depicts certain metabolites of exemplary compounds of the disclosure.
  • FIG.10A depicts the activities of exemplary compounds of the disclosure against HK301.
  • FIG.10B depicts the activities of exemplary compounds of the disclosure against GBM39.
  • FIG.10C depicts the activities of exemplary compounds of the disclosure against NHA.
  • FIG.11A decpits the ADME characteristics of an exemplary compound of the disclosure in rats following PO admistration.
  • FIG.11B decpits the ADME characteristics of an exemplary compound of the disclosure in rats following PO admistration.
  • FIG.12A depicts the activity of certain compounds of the disclosure as compared against the current standard of care (i.e., Labpatinib, Erlotinib, Gefitinib, and AZD3759) against HK301, a patient derived, EGFRvIII mutant GBM gliomasphere.
  • the current standard of care i.e., Labpatinib, Erlotinib, Gefitinib, and AZD3759
  • FIG.12B depicts the activity of certain compounds of the disclosure as compared against the current standard of care (i.e., Labpatinib, Erlotinib, Gefitinib, and AZD3759) against HK301, a patient derived, EGFRvIII mutant GBM gliomasphere.
  • FIG.13A depicts the activity of certain compounds of the disclosure as compared against the current standard of care (i.e., Labpatinib, Erlotinib, Gefitinib, and AZD3759) against GBM39, a patient derived, EGFRvIII mutant GBM gliomasphere.
  • FIG.13B depicts the activity of certain compounds of the disclosure as compared against the current standard of care (i.e., Labpatinib, Erlotinib, Gefitinib, and AZD3759) against GBM39, a patient derived, EGFRvIII mutant GBM gliomasphere.
  • FIG.14A depicts the activity of osimertinib and JGK068S against pEGFRwt.
  • FIG. 14B depicts the activity of osimertinib and JGK068S against pEGFRvIII.
  • FIG.15A depicts the activity of osimertinib and JGK068S against HK301.
  • FIG.15B depicts the activity of osimertinib and JGK068S against GBM39.
  • FIG.16A depicts the activity of AZD3759, AZD9291, and JGK068S against certain EGFR mutants.
  • FIG.16B depicts the activity of AZD3759, AZD9291, and JGK068S against pEGFR A263P.
  • FIG.16C depicts the activity of AZD3759, AZD9291, and JGK068S against pEGFR A289V.
  • FIG.16D depicts the activity of AZD3759, AZD9291, and JGK068S against pEGFR A289D.
  • FIG.16E depicts the activity of AZD3759, AZD9291, and JGK068S against pEGFR G598V.
  • DETAILED DESCRIPTION OF THE DISCLOSURE Gliomas are the most commonly occurring form of brain tumor, with glioblastoma multiforme (GBM) being most malignant form, causing 3–4% of all cancer-related deaths (Louis et al. (2007) Acta. Neuropathol.114: 97-109.).
  • GBM glioblastoma multiforme
  • the World Health Organization defines GBM as a grade IV cancer characterized as malignant, mitotically active, and predisposed to necrosis.
  • GBM has a very poor prognosis with a 5-year survival rate of 4–5% with the median survival rate of GBM being 12.6 months (McLendon et al. (2003) Cancer. 98 :1745-1748.). This can be attributed to unique treatment limitations such as a high average age of onset, tumor location, and poor current understandings of the tumor pathophysiology (Louis et al. (2007) Acta. Neuropathol.114: 97-109). The current standard of care for GBM includes tumor resection with concurrent radiotherapy and chemotherapy and in recent years there have been few marked improvements that increase survival rates (Stewart, et al. (2002) Lancet.359:1011-1018.).
  • TMZ temozolomide
  • a or G purines
  • TMZ use has drawbacks in that significant risk arises from DNA damage in healthy cells and that GBM cells can rapidly develop resistance towards the drug (Carlsson, et al. (2014) EMBO. Mol. Med.6: 1359- 1370). As such, additional chemotherapy options are urgently required.
  • EGFR is a member of the HER superfamily of receptor tyrosine kinases together with ERBB2, ERBB3, and ERBB4.
  • EGFR amplification is found in nearly 40% of all GBM cases (Hynes et al. (2005) Nat. Rev. Cancer.5: 341-354; Hatanpaa et al. (2010) Neoplasia.12 :675-684). Additionally, EGFR amplification is associated with the presence of EGFR protein variants: in 68% of EGFR mutants there is a deletion in the N-terminal ligand-binding region between amino acids 6 and 273. These deletions in the ligand-binding domains of EGFR can lead to ligand- independent activation of EGFR (Yamazaki et al. (1990) Jpn. J. Cancer Res.81: 773-779.).
  • R 1 is selected from the group consisting of R 2 is selected from C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl, each of which is optionally substituted with one or more halogen, or a pharmaceutically acceptable salt thereof.
  • R 1 is , or a pharmaceutically acceptable salt thereof.
  • R 1 is , or a pharmaceutically acceptable salt thereof.
  • R 1 is , or a pharmaceutically acceptable salt thereof. In yet other embodiments, R 1 is , or a pharmaceutically acceptable salt thereof. In yet other embodiments, R 1 is , or a pharmaceutically acceptable salt thereof. In yet other embodiments, is , or a pharmaceutically acceptable salt thereof.
  • R 2 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, trifluoromethyl, fluoroethyl, and difluoroethyl, or a pharmaceutically acceptable salt thereof.
  • R 2 is selected from methyl, ethyl, n-propyl, isopropyl, tert-butyl, fluoroethyl, and difluoroethyl, or a pharmaceutically acceptable salt thereof.
  • R 2 is methyl, or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides compounds having a structure represented by Formula (Ia): wherein: R 1 is selected from the group consisting of R 2 is selected from C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl, each of which is optionally substituted with one or more halogen, or a pharmaceutically acceptable salt thereof.
  • R 1 is , or a pharmaceutically acceptable salt thereof. In other embodiments, R 1 is , or a pharmaceutically acceptable salt thereof. In yet other embodiments, R 1 is , or a pharmaceutically acceptable salt thereof. In yet other embodiments, R 1 is , or a pharmaceutically acceptable salt thereof. In yet other embodiments, R 1 is , or a pharmaceutically acceptable salt thereof. In yet other embodiments, is , or a pharmaceutically acceptable salt thereof.
  • R 2 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, trifluoromethyl, fluoroethyl, and difluoroethyl, or a pharmaceutically acceptable salt thereof.
  • R 2 is selected from methyl, ethyl, n-propyl, isopropyl, tert-butyl, fluoroethyl, and difluoroethyl, or a pharmaceutically acceptable salt thereof.
  • R 2 is methyl, or a pharmaceutically acceptable salt thereof.
  • R 1 is selected from the group consisting of R 2 is selected from C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl, each of which is optionally substituted with one or more halogen, or a pharmaceutically acceptable salt thereof.
  • R 1 is , or a pharmaceutically acceptable salt thereof.
  • R 1 is , or a pharmaceutically acceptable salt thereof.
  • R 1 is , or a pharmaceutically acceptable salt thereof.
  • R 1 is , or a pharmaceutically acceptable salt thereof.
  • R 1 is , or a pharmaceutically acceptable salt thereof.
  • R 1 is , or a pharmaceutically acceptable salt thereof.
  • R 2 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, trifluoromethyl, fluoroethyl, and difluoroethyl, or a pharmaceutically acceptable salt thereof.
  • R 2 is selected from methyl, ethyl, n-propyl, isopropyl, tert-butyl, fluoroethyl, and difluoroethyl, or a pharmaceutically acceptable salt thereof.
  • R 2 is methyl, or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I), (Ia), or (Ib) is enantiomerically enriched.
  • the compound of Formula (I), (Ia), or (Ib) is diastereomerically enriched.
  • the compound of Formula (I), (Ia), or (Ib) is in the form of a pharmaceutically acceptable salt.
  • the compound is in the form of a free base.
  • the compound of the disclosure is selected from or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides methods of treating a disorder or condition in a subject in need thereof by modulation of an epidermal growth factor receptor, the method comprising administering to the subject an amount of a compound or composition of the disclosure, thereby treating the disorder or condition.
  • the present disclosure provides methods of treating a disorder or condition in a subject in need thereof by antagonizing an epidermal growth factor receptor, the method comprising administering to the subject an amount of a compound or composition of the disclosure, thereby treating the disorder or condition.
  • the present disclosure provides methods of inhibiting EGFR or a variant thereof in a subject, comprising administering to the subject a compound or composition of the disclosure.
  • the EGFR or a variant thereof is ⁇ EGFR, an ex19 deletion, an EGFRvIII high-expression variant, or one or more EGFR amino acid mutants.
  • the one or more EGFR amino acid mutants is selected from L858R, C787S, C797X, L718Q, G724S, S768I, G719X, L792X, G796X, T263P, A289D, A289V, and G598V.
  • the one or more EGFR amino acid mutants is selected from C797S, G719A, L792H, L792F, L792Y, G796R and G796S.
  • the present disclosure provides methods of treating cancer in a subject, comprising of administering to the subject in need of a treatment for cancer a compound or composition of the disclosure.
  • the cancer is bladder cancer, bone cancer, brain cancer, breast cancer, cardiac cancer, cervical cancer, colon cancer, rectal cancer, colorectal cancer, esophageal cancer, fibrosarcoma, gastric cancer, gastrointestinal cancer, head, spine and neck cancer, Kaposi's sarcoma, kidney cancer, leukemia, liver cancer, lymphoma, melanoma, multiple myeloma, pancreatic cancer, penile cancer, testicular germ cell cancer, thymoma carcinoma, thymic carcinoma, lung cancer, ovarian cancer, prostate cancer, CNS cancer, non- CNS cancer, or CNS metastases.
  • the cancer is lung cancer, colon cancer, rectal cancer, colorectal cancer, esophageal cancer, and pancreatic cancer.
  • the cancer is lung cancer.
  • the cancer is colon cancer.
  • the cancer is rectal cancer.
  • the cancer is colorectal cancer.
  • the cancer is esophageal cancer.
  • the cancer is pancreatic cancer.
  • the cancer is glioma, astrocytoma or glioblastoma.
  • the cancer is glioma.
  • the cancer is astrocytoma.
  • the astrocytoma is low- grade astrocytoma, mixed oligoastrocytoma, pilocytic astrocytoma, pleomorphic xanthoastrocytoma, subependymal giant cell astrocytoma, or anaplastic astrocytoma.
  • the cancer is glioblastoma.
  • the present disclosure provides methods of reducing glioblastoma proliferation in a subject, comprising administering to the subject an amount of a compound or composition of the disclosure. In certain embodiments, the method further comprises administering to the subject a MDM2 inhibitor.
  • the present disclosure provides methods of reducing glioblastoma proliferation in a subject, comprising administering to the subject an effective amount of a compound or composition of the disclosure and a second agent selected from an MDM2 inhibitor, a BCL-xL inhibitor, or a BCL-2 inhibitor, after determining that the glucose metabolism in a sample taken from the subject is susceptible to a glucose metabolism inhibitor.
  • the present disclosure provides methods for treating cancer or reducing cancer cell proliferation in a subject that has been determined to have cancer that is responsive to a glucose metabolism inhibitor, comprising administering to the subject an amount of a compound or composition of the disclosure and a p53 stabilizer.
  • the present disclosure provides methods for treating malignant glioma or glioblastoma in a subject, comprising administering to the subject an amount of a compound or composition of the disclosure and a p53 stabilizer.
  • the subject has been determined to be susceptible to the glucose metabolism inhibitor by a method comprising: a. obtaining a tumor biopsy from the subject; b. measuring the level of glucose uptake by the tumor cells in the presence of the glucose metabolism inhibitor; c. comparing the level of glucose uptake by the tumor cells obtained in step b. to the level of glucose uptake by a control; and d.
  • the method further comprises detecting the 18F-FDG by positron emission tomography (PET).
  • PET positron emission tomography
  • the reduction in the glucose level between the second blood sample and the first blood sample is about or greater than 0.15 mM. In certain embodiments, the reduction in the glucose level between the second blood sample and the first blood sample is about or greater than 0.20 mM.
  • the reduction in the glucose level between the second blood sample and the first blood sample is in the range of 0.15 mM - 2.0 mM. In cetain embodiments, the reduction in the glucose level between the second blood sample and the first blood sample is in the range of 0.25 mM - 1.0 mM.
  • the subject has been determined to be susceptible to the glucose metabolism inhibitor by a method comprising: a. obtaining a first blood sample from the subject; b. placing the subject on a ketogenic diet; c. obtaining a second blood sample from the subject after being placed on a ketogenic diet for a period of time; d. measuring glucose level in the first and in the second blood sample; e.
  • the reduction in the glucose level between the second blood sample and the control blood sample is about or greater than 0.15 mM. In certain embodiments, the reduction in the glucose level between the second blood sample and the control blood sample is about or greater than 0.20 mM. In certain embodiments, the reduction in the glucose level between the second blood sample and the control blood sample is in the range of 0.15 mM - 2.0 mM.
  • the reduction in the glucose level between the second blood sample and the control blood sample is in the range of 0.25 mM - 1.0 mM.
  • the compound or composition of the disclosure and the p53 stabilizer are administered to the subject in the same composition.
  • the compound or composition according of the disclosure and the p53 stabilizer are administered to the subject conjointly.
  • the compound or composition of the disclosure and the p53 stabilizer are administered to the subject within 24 hours of each other.
  • the compound or composition of the disclosure and the p53 stabilizer are administered to the subject within 6 hours of each other.
  • the compound or composition of the disclosure and the p53 stabilizer are administered to the subject within 2 hours of each other. In certain embodiments, the compound or composition of the disclosure and the p53 stabilizer are administered to the subject within 1 hour of each other. In certain embodiments, the compound or composition of the disclosure and the p53 stabilizer are administered to the subject within 30 minutes of each other. In certain embodiments, the compound or composition of the disclosure and the p53 stabilizer are administered to the subject at the same time. In certain embodiments of the methods disclosed herein, the subject has been diagnosed with glioblastoma multiforme. In certain embodiments, the subject has been previously treated for glioblastoma with a prior treatment.
  • the subject has been determined to be resistant to the prior treatment.
  • the methods disclosed herein further comprise administering to the subject of one or more additional therapeutic agents.
  • the p53 stabilizer is an MDM2 inhibitor or antagonist.
  • the MDM2 inhibitor is a nutlin.
  • the MDM2 inhibitor is nutlin-3 or idasanutlin.
  • the MDM2 inhibitor is RO5045337, RO5503781, R06839921, SAR405838, DS-3032, DS-3032b, or AMG-232.
  • the p53 stabilizer is a BCL-2 inhibitor.
  • the BCL-2 inhibitor is antisense oligodeoxynucleotide G3139, mRNA antagonist SPC2996, venetoclax (ABT-199), GDC-0199, obatoclax, paclitaxel, navitoclax (ABT-263), ABT-737, NU-0129, S 055746, or APG-1252.
  • the p53 stabilizer is a Bcl-xL inhibitor.
  • the Bcl-xL inhibitor is WEHI 539, ABT-263, ABT-199, ABT-737, sabutoclax, AT101, TW-37, APG- 1252, or gambogic acid.
  • the methods disclosed herein further comprise administering to the subject of one or more additional therapeutic agents.
  • the one or more additional therapeutic agents is selected from KRAS G12C inhibitors, EGFR inhibitors, SHP2 inhibitors, CDK4/6 inhibitors, ERK inhibitors, MEK inhibitors, and MET inhibitors.
  • the one or more additional therapeutic agents is selected from one or more KRAS G12C inhibitors.
  • the one or more KRAS G12C inhibitors is selected from AMG 510, MRTX849, and GDC-6036.
  • the one or more KRAS G12C inhibitors is AMG510.
  • the one or more KRAS G12C inhibitors is MRTX849. In certain embodiments, the one or more KRAS G12C inhibitors is GDC-6036. In certain embodiments, the one or more additional therapeutic agents is selected from one or more EGFR inhibitors.
  • the one or more EGFR inhibitors is selected from osimertinib, afatinib, erlotinib, gefitinib, lazertinib, soloartinib, dacomitinib, BLU-945, icotinib, cetuximab, paninitumab, amivantamab, lapatinib, neratinib, zorifertinib, and mobicertinib.
  • the one or more additional therapeutic agents is selected from one or more SHP2 inhibitors.
  • the one or more EGFR inhibitors is osimertinib.
  • the one or more EGFR inhibitors is afatinib. In certain embodiments, the one or more EGFR inhibitors is erlotinib. In certain embodiments, the one or more EGFR inhibitors is gefitinib. In certain embodiments, the one or more EGFR inhibitors is lazertinib. In certain embodiments, the one or more EGFR inhibitors is soloartinib. In certain embodiments, the one or more EGFR inhibitors is dacomitinib. In certain embodiments, the one or more EGFR inhibitors is BLU-945. In certain embodiments, the one or more EGFR inhibitors is icotinib.
  • the one or more EGFR inhibitors is cetuximab. In certain embodiments, the one or more EGFR inhibitors is paninitumab. In certain embodiments, the one or more EGFR inhibitors is amivantamab. In certain embodiments, the one or more EGFR inhibitors is lapatinib. In certain embodiments, the one or more EGFR inhibitors is neratinib. In certain embodiments, the one or more EGFR inhibitors is zorifertinib. In certain embodiments, the one or more EGFR inhibitors is mobicertinib.
  • the one or more SHP2 inhibitors is selected from ERAS-601, TNO155, RMC-4630, JAB-3068, JAB-3312, and RLY-1971.
  • the one or more SHP2 inhibitors is ERAS-601.
  • the one or more SHP2 inhibitors is TNO155.
  • one or more SHP2 inhibitors is RMC-4630.
  • the one or more SHP2 inhibitors is JAB-3068.
  • the one or more SHP2 inhibitors is JAB-3312.
  • the one or more SHP2 inhibitors is RLY-1971.
  • the one or more additional therapeutic agents is selected from one or more CDK4/6 inhibitors.
  • the one or more CDK4/6 inhibitors is selected from palbociclib, abemaciclib, and ribociclib. In certain embodiments, the one or more CDK4/6 inhibitors is palbociclib. In certain embodiments, the one or more CDK4/6 inhibitors is abemaciclib. In certain embodiments, the one or more CDK4/6 inhibitors is ribociclib. In certain embodiments, the one or more additional therapeutic agents is selected from one or more ERK inhibitors. In certain embodiments, the one or more ERK inhibitors is selected from ulixertinib, ASN007, LY3214996, and LTT462. In certain embodiments, the one or more ERK inhibitors is ulixertinib.
  • the one or more ERK inhibitors is ASN007. In certain embodiments, the one or more ERK inhibitors is LY3214996. In certain embodiments, he one or more ERK inhibitors is LTT462. In certain embodiments, the one or more additional therapeutic agents is selected from one or more MEK inhibitors. In certain embodiments, the one or more MEK inhibitors is selected from trametinib, binimetinib, cobimetinib, and selumetinib. In certain embodiments, the one or more MEK inhibitors is trametinib. In certain embodiments, the one or more MEK inhibitors is binimetinib.
  • the one or more MEK inhibitors is cobimetinib. In certain embodiments, the one or more MEK inhibitors is selumetinib.In certain embodiments, the one or more additional therapeutic agents is selected from one or more MET inhibitors. In certain embodiments, the one or more MET inhibitors is selected from capmatinib, crizotinib, and savolitinib. In certain embodiments, the one or more MET inhibitors is capmatinib. In certain embodiments, the one or more MET inhibitors is crizotinib. In certain embodiments, the one or more MET inhibitors is savolitinib. In yet another aspect, the present disclosure provides compounds or compositions for use as a medicament.
  • the medicament is used in the treatment of cancer in a subject.
  • the cancer is bladder cancer, bone cancer, brain cancer, breast cancer, cardiac cancer, cervical cancer, colon cancer, rectal cancer, colorectal cancer, esophageal cancer, fibrosarcoma, gastric cancer, gastrointestinal cancer, head, spine and neck cancer, Kaposi's sarcoma, kidney cancer, leukemia, liver cancer, lymphoma, melanoma, multiple myeloma, pancreatic cancer, penile cancer, testicular germ cell cancer, thymoma carcinoma, thymic carcinoma, lung cancer, ovarian cancer, prostate cancer, CNS cancer, non-CNS cancer, or CNS metastases.
  • the cancer is lung cancer, colon cancer, rectal cancer, colorectal cancer, esophageal cancer, and pancreatic cancer.
  • the cancer is lung cancer.
  • the cancer is colon cancer.
  • the cancer is rectal cancer.
  • the cancer is colorectal cancer.
  • the cancer is esophageal cancer.
  • the cancer is pancreatic cancer.
  • the cancer is glioma, astrocytoma or glioblastoma.
  • the cancer is glioma.
  • the cancer is astrocytoma.
  • the astrocytoma is low-grade astrocytoma, mixed oligoastrocytoma, pilocytic astrocytoma, pleomorphic xanthoastrocytoma, subependymal giant cell astrocytoma, or anaplastic astrocytoma.
  • the cancer is glioblastoma.
  • Types and stages of Gliomas Primary malignant brain tumors are tumors that start in the brain or spine are known collectively as gliomas. Gliomas are not a specific type of cancer but are a term used to describe tumors that originate in glial cells.
  • Examples of primary malignant brain tumors include astrocytomas, pilocytic astrocytomas, pleomorphic xanthoastrocytomas, diffuse astrocytomas, anaplastic astrocytomas, GBMs, gangliogliomas, oligodendrogliomas, ependymomas.
  • astrocytomas According to the WHO classification of brain tumors, astrocytomas have been categorized into four grades, determined by the underlying pathology. The characteristics that are used to classify gliomas include mitoses, cellular or nuclear atypia, and vascular proliferation and necrosis with pseudopalisading features.
  • Malignant (or high- grade) gliomas include anaplastic glioma (WHO grade III) as well as glioblastoma multiforme (GBM; WHO grade IV). These are the most aggressive brain tumors with the worst prognosis. GBMs is the most common, complex, treatment resistant, and deadliest type of brain cancer, accounting for 45% of all brain cancers, with nearly 11,000 men, women, and children diagnosed each year. GBM (also known as grade-4 astrocytoma and glioblastoma multiforme) are the most common types of malignant (cancerous) primary brain tumors. They are extremely aggressive for a number of reasons. First, glioblastoma cells multiply quickly, as they secrete substances that stimulate a rich blood supply.
  • GBM glioblastomas
  • Primary GBM are the most common form; they grow quickly and often cause symptoms early. Secondary glioblastomas are less common, accounting for about 10 percent of all GBMs. They progress from low-grade diffuse astrocytoma or anaplastic astrocytoma, and are more often found in younger patients. Secondary GBM are preferentially located in the frontal lobe and carry a better prognosis. GBM is usually treated by combined multi-modal treatment plan including surgical removal of the tumor, radiation and chemotherapy. First, as much tumor as possible is removed during surgery.
  • the oral chemotherapy drug temozolomide
  • temozolomide is most often used for six weeks, and then monthly thereafter.
  • bevacizumab is also used during treatment. This drug attacks the tumor’s ability to recruit blood supply, often slowing or even stopping tumor growth. Novel investigational treatments are also used and these may involve adding treatments to the standard therapy or replacing one part of the standard therapy with a different treatment that may work better.
  • Some of these treatments include immunotherapy such as vaccine immunotherapies, or low-dose pulses of electricity to the area of the brain where the tumor exists and nano therapies involving spherical nucleic acids (SNAs) such as NU-0129.
  • the methods of the current disclosure are used in combination with one or more of the aforementioned therapies.
  • Methods of Assessment Glucose Uptake Tests In embodiments of the methods and compositions of the current disclosure, the subject with GBM or cancer is classified to be either a “metabolic responder” or a “metabolic non-responder” i.e. determined to be susceptible to glucose metabolism inhibitors.
  • the classification of the subject is prior to administering to the subject a treatment comprising a glucose metabolism inhibitor and a cytoplasmic p53 stabilizer.
  • a treatment comprising a glucose metabolism inhibitor and a cytoplasmic p53 stabilizer.
  • the current disclosure provides for methods for assessing a cancer, classifying a subject, determining the susceptibility of a subject to treatments involve analysis of glucose metabolism, glycolysis or glucose uptake. Methods to classify a subject as metabolic responder is described in details in Example 1. Techniques to monitor glycolysis and glucose uptake is provided by T. TeSlaa and M.A. Teitell.2014. Methods in Enzymology, Volume 542, pp.92-114, incorporated herein by reference.
  • Glycolysis is the intracellular biochemical conversion of one molecule of glucose into two molecules of pyruvate with the concurrent generation of two molecules of ATP.
  • Pyruvate is a metabolic intermediate with several potential fates including entrance into the tricarboxylic acid (TCA) cycle within mitochondria to produce NADH and FADH 2 .
  • TCA tricarboxylic acid
  • pyruvate can be converted into lactate in the cytosol by lactate dehydrogenase with concurrent regeneration of NAD + from NADH.
  • An increased flux through glycolysis supports the proliferation of cancer cells by providing, for example, additional energy in the form of ATP as well as glucose-derived metabolic intermediates for nucleotide, lipid, and protein biosynthesis.
  • Warburg Oncologia.1956;9(2):75-873 first observed that proliferating tumor cells augment aerobic glycolysis, the conversion of glucose to lactate in the presence of oxygen, in contrast to nonmalignant cells that mainly respire when oxygen is available. This mitochondrial bypass, called the Warburg effect, occurs in rapidly proliferating cells including cancer cells, activated lymphocytes, and pluripotent stem cells.
  • the Warburg effect has been exploited for clinical diagnostic tests that use positron emission tomography (PET) scanning to identify increased cellular uptake of fluorinated glucose analogs such as 2-deoxy- 2-( 18 F)-fluoro-D-glucose (also referred to herein as 18 F-deoxyglucose, 18 F-FDG, 18 FDG, or FDG) .
  • PET positron emission tomography
  • 18 F-deoxyglucose also referred to herein as 18 F-deoxyglucose, 18 F-FDG, 18 FDG, or FDG
  • glycolysis represent a target for therapeutic and diagnostic methods.
  • the measurement of glucose uptake and lactate excretion by malignant cells may be useful to detect shifts in glucose catabolism and/or susceptibility to glucose metabolism inhibitors.
  • 18 F-deoxyglucose PET serves in certain embodiments as a rapid non-invasive functional biomarker to predict sensitivity to p53 activation. This non-invasive anlaysis could be particularly valuable for malignant brain tumors where pharmacokinetic/pharmacodynamics assessment is extremely difficult and impractical.
  • delayed imaging protocols (41) and parametric response maps (PRMs) with MRI fusion can be useful for quantifying the changes in tumore 18 F-FDG uptake (42).
  • the methods can relate to measuring glucose uptake and lactate production.
  • glycolytic flux can be quantified by measuring glucose uptake and lactate excretion.
  • Glucose uptake into the cell is through glucose transporters (Glut1–Glut4), whereas lactate excretion is through monocarboxylate transporters (MCT1– MCT4) at the cell membrane.
  • Extracellular glucose and lactate Methods to detect glucose uptake and lactate excretion include, for example, extracellular glucose or lactate kit, extracellular bioanalyzer, ECAR measurement, [3H]-2- DG or [14C]-2-DG uptake 18 FDG uptake or 2-NBDG uptake.
  • kits and instruments are available to quantify glucose and lactate levels within cell culture media.
  • Kit detection methods are usually colorimetric or fluorometric and are compatible with standard lab equipment such as spectrophotometers.
  • BioProfile Analyzers such as Nova Biomedical
  • Biochemistry Analyzers such as for example YSI Life Sciences
  • GlucCell can measure only glucose levels in cell culture media. While each commercial method has a different detection protocol, the collection of culture media for analysis is the same.
  • Extracellular acidification rate Glycolysis can also be determined through measurements of the extracellular acidification rate (ECAR) of the surrounding media, which is predominately from the excretion of lactic cid per unit time after its conversion from pyruvate.
  • ECAR extracellular acidification rate
  • the Seahorse extracellular flux (XF) analyzer (Seahorse Bioscience) is a tool for measuring glycolysis and oxidative phosphorylation (through oxygen consumption) simultaneously in the same cells.
  • Glucose analog uptake Certain embodiments of the methods of the current disclosure include the use of glucose analogs. As would be familiar to a person skilled in the art, to determine the glucose uptake rate by cells, a labeled isoform of glucose can be added to the cell culture media and then measured within cells after a given period of time.
  • glucose analogs for these studies include but are not limited to radioactive glucose analogs, such as 2-deoxy- D-[1,2-3H]-glucose, 2-deoxy-D-[1-14C]-glucose, or 2-deoxy-2-( 18 F)-fluoro-D-glucose ( 18 FDG), or fluorescent glucose analogs, such as 2-[N-(7-nitrobenz-2-oxa-1,3-diaxol-4- yl)amino]-2-deoxyglucose (2-NBDG).
  • radioactive glucose analogs such as 2-deoxy- D-[1,2-3H]-glucose, 2-deoxy-D-[1-14C]-glucose, or 2-deoxy-2-( 18 F)-fluoro-D-glucose ( 18 FDG)
  • fluorescent glucose analogs such as 2-[N-(7-nitrobenz-2-oxa-1,3-diaxol-4- yl)amino]-2-deoxygluco
  • the glucose uptake is measured by the uptake of radio-labelled glucose 2-deoxy-2-[fluorine-18]fluoro-D-glucose ( 18 F-FDG).
  • detecting the 18 F-FDG is by positron emission tomography (PET).
  • PET positron emission tomography
  • the biopsy is taken from a GBM tumor. A detailed description of an example of measuring 18 F-FDG is provided in the examples below.
  • the methods can relate to comparing glucose uptake of a biological sample such as a tumor sample with a control.
  • Fold increases or decreases may be, be at least, or be at most 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13-, 14-, 15-, 16-, 17-, 18-, 19-, 20-, 25-, 30-, 35-, 40-, 45-, 50-, 55-, 60-, 65-, 70-, 75-, 80-, 85-, 90-, 95-, 100- or more, or any range derivable therein.
  • differences in expression between a sample and a reference may be expressed as a percent decrease or increase, such as at least or at most 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 300, 400, 500, 600, 700, 800, 900, 1000% difference, or any range derivable therein.
  • the levels can be relative to a control.
  • Algorithms such as the weighted voting programs, can be used to facilitate the evaluation of biomarker levels.
  • other clinical evidence can be combined with the biomarker-based test to reduce the risk of false evaluations.
  • Other cytogenetic evaluations may be considered in some embodiments.
  • Pharmaceutical Compositions The compositions and methods of the present disclosure may be utilized to treat an individual in need thereof.
  • the individual is a mammal such as a human, or a non-human mammal.
  • the composition or the compound is preferably administered as a pharmaceutical composition comprising, for example, a compound of the disclosure and a pharmaceutically acceptable carrier.
  • Pharmaceutically acceptable carriers include, for example, aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters.
  • aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters.
  • the aqueous solution is pyrogen-free, or substantially pyrogen-free.
  • the excipients can be chosen, for example, to effect delayed release of an agent or to selectively target one or more cells, tissues or organs.
  • the pharmaceutical composition can be in dosage unit form such as tablet, capsule (including sprinkle capsule and gelatin capsule), granule, lyophile for reconstitution, powder, solution, syrup, suppository, injection or the like.
  • the composition can also be present in a transdermal delivery system, e.g., a skin patch.
  • the composition can also be present in a solution suitable for topical administration, such as a lotion, cream, or ointment.
  • a pharmaceutically acceptable carrier can contain physiologically acceptable agents that act, for example, to stabilize, increase solubility or to increase the absorption of a compound such as a compound of the disclosure.
  • physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients.
  • a pharmaceutically acceptable carrier including a physiologically acceptable agent, depends, for example, on the route of administration of the composition.
  • the preparation or pharmaceutical composition can be a selfemulsifying drug delivery system or a selfmicroemulsifying drug delivery system.
  • the pharmaceutical composition (preparation) also can be a liposome or other polymer matrix, which can have incorporated therein, for example, a compound of the disclosure.
  • Liposomes for example, which comprise phospholipids or other lipids, are nontoxic, physiologically acceptable and metabolizable carriers that are relatively simple to make and administer.
  • pharmaceutically acceptable is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable carrier as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and eth
  • a pharmaceutical composition can be administered to a subject by any of a number of routes of administration including, for example, orally (for example, drenches as in aqueous or non-aqueous solutions or suspensions, tablets, capsules (including sprinkle capsules and gelatin capsules), boluses, powders, granules, pastes for application to the tongue); absorption through the oral mucosa (e.g., sublingually); subcutaneously; transdermally (for example as a patch applied to the skin); and topically (for example, as a cream, ointment or spray applied to the skin).
  • the compound may also be formulated for inhalation.
  • a compound may be simply dissolved or suspended in sterile water.
  • compositions suitable for same can be found in, for example, U.S. Pat. Nos.6,110,973, 5,763,493, 5,731,000, 5,541,231, 5,427,798, 5,358,970 and 4,172,896, as well as in patents cited therein.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration.
  • the amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect.
  • compositions Generally, out of one hundred percent, this amount will range from about 1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.
  • Methods of preparing these formulations or compositions include the step of bringing into association an active compound, such as a compound of the disclosure, with the carrier and, optionally, one or more accessory ingredients.
  • the formulations are prepared by intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • Formulations of the disclosure suitable for oral administration may be in the form of capsules (including sprinkle capsules and gelatin capsules), cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), lyophile, powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in- water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present disclosure as an active ingredient.
  • capsules including sprinkle capsules and gelatin capsules
  • cachets pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth)
  • lyophile powders,
  • compositions or compounds may also be administered as a bolus, electuary or paste.
  • solid dosage forms for oral administration capsules (including sprinkle capsules and gelatin capsules), tablets, pills, dragees, powders, granules and the like)
  • the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6)
  • the pharmaceutical compositions may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets, and other solid dosage forms of the pharmaceutical compositions such as dragees, capsules (including sprinkle capsules and gelatin capsules), pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres.
  • compositions may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
  • These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner.
  • embedding compositions that can be used include polymeric substances and waxes.
  • the active ingredient can also be in micro- encapsulated form, if appropriate, with one or more of the above-described excipients.
  • Liquid dosage forms useful for oral administration include pharmaceutically acceptable emulsions, lyophiles for reconstitution, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, cyclodextrins and derivatives thereof, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art, such
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • Dosage forms for the topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be required.
  • the ointments, pastes, creams and gels may contain, in addition to an active compound, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays can contain, in addition to an active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound of the present disclosure to the body. Such dosage forms can be made by dissolving or dispersing the active compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.
  • parenteral administration and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.
  • compositions suitable for parenteral administration comprise one or more active compounds in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
  • aqueous and nonaqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents.
  • microorganisms Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions.
  • isotonic agents such as sugars, sodium chloride, and the like into the compositions.
  • prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin.
  • the rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form.
  • delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
  • injectable depot forms are made by forming microencapsulated matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides).
  • Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissue.
  • active compounds can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.
  • Methods of introduction may also be provided by rechargeable or biodegradable devices.
  • Various slow release polymeric devices have been developed and tested in vivo in recent years for the controlled delivery of drugs, including proteinaceous biopharmaceuticals.
  • biocompatible polymers including hydrogels
  • biodegradable and non-degradable polymers can be used to form an implant for the sustained release of a compound at a particular target site.
  • Actual dosage levels of the active ingredients in the pharmaceutical compositions may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • the selected dosage level will depend upon a variety of factors including the activity of the particular compound or combination of compounds employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound(s) being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound(s) employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
  • a physician or veterinarian having ordinary skill in the art can readily determine and prescribe the therapeutically effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the pharmaceutical composition or compound at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
  • terapéuticaally effective amount is meant the concentration of a compound, drug, or agent that is sufficient to elicit the desired therapeutic effect.
  • the full therapeutic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses.
  • a therapeutically effective amount may be administered in one or more administrations. It is generally understood that the effective amount of the compound will vary according to the weight, sex, age, and medical history of the subject, and the nature and extent of the condition being treated, such as cancer. Other factors which influence the effective amount may include, but are not limited to, the severity of the patient's condition, the disorder being treated, the stability of the compound, and, if desired, another type of therapeutic agent being administered with the compound of the disclosure.
  • a larger total dose can be delivered by multiple administrations of the agent.
  • Methods to determine efficacy and dosage are known to those skilled in the art (Isselbacher et al. (1996) Harrison’s Principles of Internal Medicine 13 ed., 1814-1882, herein incorporated by reference). The skilled worker can readily determine the effective amount for a given situation by routine experimentation
  • a suitable daily dose of an active compound used in the compositions and methods of the disclosure will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.
  • the effective daily dose of the active compound may be administered as one, two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms.
  • the active compound may be administered two or three times daily.
  • the active compound will be administered once daily.
  • the patient receiving this treatment is any animal in need, including primates, in particular humans; and other mammals such as equines, cattle, swine, sheep, cats, and dogs; poultry; and pets in general.
  • compounds of the disclosure may be used alone or conjointly administered with another type of therapeutic agent.
  • the present disclosure includes the use of pharmaceutically acceptable salts of compounds of the disclosure in the compositions and methods of the present disclosure.
  • contemplated salts of the disclosure include, but are not limited to, alkyl, dialkyl, trialkyl or tetra-alkyl ammonium salts.
  • contemplated salts of the disclosure include, but are not limited to, L-arginine, benenthamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2- (diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, 1H-imidazole, lithium, L-lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine, potassium, 1-(2-hydroxyethyl)pyrrolidine, sodium, triethanolamine, tromethamine, and zinc salts.
  • contemplated salts of the disclosure include, but are not limited to, Na, Ca, K, Mg, Zn or other metal salts.
  • contemplated salts of the disclosure include, but are not limited to, 1-hydroxy-2-naphthoic acid, 2,2- dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, l-ascorbic acid, l-aspartic acid, benzenesulfonic acid, benzoic acid, (+)-camphoric acid, (+)-camphor-10-sulfonic acid, capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, e
  • the pharmaceutically acceptable acid addition salts can also exist as various solvates, such as with water, methanol, ethanol, dimethylformamide, and the like. Mixtures of such solvates can also be prepared.
  • the source of such solvate can be from the solvent of crystallization, inherent in the solvent of preparation or crystallization, or adventitious to such solvent.
  • Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
  • antioxidants examples include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal-chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
  • water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like
  • oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), le
  • agent is used herein to denote a chemical compound (such as an organic or inorganic compound, a mixture of chemical compounds), a biological macromolecule (such as a nucleic acid, an antibody, including parts thereof as well as humanized, chimeric and human antibodies and monoclonal antibodies, a protein or portion thereof, e.g., a peptide, a lipid, a carbohydrate), or an extract made from biological materials such as bacteria, plants, fungi, or animal (particularly mammalian) cells or tissues.
  • Agents include, for example, agents whose structure is known, and those whose structure is not known. The ability of such agents to inhibit EGFR may render them suitable as “therapeutic agents” in the methods and compositions of this disclosure.
  • the compounds or compositions of the disclosure inhibit EGFR or a variant thereof.
  • the EGFR or a variant thereof is ⁇ EGFR, an ex19 deletion, an EGFRvIII high-expression variant, or one or more EGFR amino acid mutants.
  • the one or more EGFR amino acid mutants is selected from L858R, C787S, C797X, L718Q, G724S, S768I, G719X, L792X, G796X, T263P, A289D, A289V, and G598V.
  • the one or more EGFR amino acid mutants is selected from C797S, G719A, L792H, L792F, L792Y, G796R and G796S.
  • a “patient,” “subject,” or “individual” are used interchangeably and refer to either a human or a non-human animal. These terms include mammals, such as humans, primates, livestock animals (including bovines, porcines, etc.), companion animals (e.g., canines, felines, etc.) and rodents (e.g., mice and rats). “Treating” a condition or patient refers to taking steps to obtain beneficial or desired results, including clinical results.
  • Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of disease, stabilized (i.e. not worsening) state of disease, preventing spread of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment.
  • preventing is art-recognized, and when used in relation to a condition, such as a local recurrence (e.g., pain), a disease such as cancer, a syndrome complex such as heart failure or any other medical condition, is well understood in the art, and includes administration of a composition which reduces the frequency of, or delays the onset of, symptoms of a medical condition in a subject relative to a subject which does not receive the composition.
  • a condition such as a local recurrence (e.g., pain)
  • a disease such as cancer
  • a syndrome complex such as heart failure or any other medical condition
  • prevention of cancer includes, for example, reducing the number of detectable cancerous growths in a population of patients receiving a prophylactic treatment relative to an untreated control population, and/or delaying the appearance of detectable cancerous growths in a treated population versus an untreated control population, e.g., by a statistically and/or clinically significant amount.
  • administering or “administration of” a substance, a compound or an agent to a subject can be carried out using one of a variety of methods known to those skilled in the art.
  • a compound or an agent can be administered, intravenously, arterially, intradermally, intramuscularly, intraperitoneally, subcutaneously, ocularly, sublingually, orally (by ingestion), intranasally (by inhalation), intraspinally, intracerebrally, and transdermally (by absorption, e.g., through a skin duct).
  • a compound or agent can also appropriately be introduced by rechargeable or biodegradable polymeric devices or other devices, e.g., patches and pumps, or formulations, which provide for the extended, slow or controlled release of the compound or agent.
  • Administering can also be performed, for example, once, a plurality of times, and/or over one or more extended periods.
  • a compound or an agent is administered orally, e.g., to a subject by ingestion.
  • the orally administered compound or agent is in an extended release, slow release formulation, delayed release, or delayed and extended release, or administered using a device for such slow release,extended release, delayed release, or delayed and extended release.
  • the phrase “conjoint administration” refers to any form of administration of two or more different therapeutic agents such that the second agent is administered while the previously administered therapeutic agent is still effective in the body (e.g., the two agents are simultaneously effective in the patient, which may include synergistic effects of the two agents).
  • the different therapeutic compounds can be administered either in the same formulation or in separate formulations, either concomitantly or sequentially.
  • an individual who receives such treatment can benefit from a combined effect of different therapeutic agents.
  • the terms “optional” or “optionally” mean that the subsequently described event or circumstance may occur or may not occur, and that the description includes instances where the event or circumstance occurs as well as instances in which it does not.
  • optionally substituted alkyl refers to the alkyl may be substituted as well as where the alkyl is not substituted. It is understood that substituents and substitution patterns on the compounds of the present disclosure can be selected by one of ordinary skilled person in the art to result in chemically stable compounds which can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure results.
  • the term “optionally substituted” refers to the replacement of one to six hydrogen radicals in a given structure with the radical of a specified substituent including, but not limited to: hydroxyl, hydroxyalkyl, alkoxy, halogen, alkyl, nitro, silyl, acyl, acyloxy, aryl, cycloalkyl, heterocyclyl, amino, aminoalkyl, cyano, haloalkyl, haloalkoxy, -OCO-CH 2 - O-alkyl, -OP(O)(O-alkyl) 2 or –CH 2 -OP(O)(O-alkyl) 2 .
  • “optionally substituted” refers to the replacement of one to four hydrogen radicals in a given structure with the substituents mentioned above. More preferably, one to three hydrogen radicals are replaced by the substituents as mentioned above. It is understood that the substituent can be further substituted.
  • alkyl refers to saturated aliphatic groups, including but not limited to C1-C10 straight-chain alkyl groups, C1-C10 branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl-substituted cycloalkyl groups, and cycloalkyl-substituted alkyl groups.
  • a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C1-30 for straight chains, C3-30 for branched chains), or 20 or fewer carbon atoms.
  • the “alkyl” group refers to C 1 -C 6 straight-chain alkyl groups or C 1 -C 6 branched-chain alkyl groups.
  • the “alkyl” group refers to C 1 - C4 straight-chain alkyl groups or C1-C4 branched-chain alkyl groups.
  • alkyl examples include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, n-butyl, sec-butyl, tert-butyl, 1-pentyl, 2-pentyl, 3-pentyl, neo-pentyl, 1-hexyl, 2-hexyl, 3-hexyl, 1-heptyl, 2-heptyl, 3- heptyl, 4-heptyl, 1-octyl, 2-octyl, 3-octyl or 4-octyl and the like.
  • the “alkyl” group may be optionally substituted.
  • alkyl as used throughout the specification, examples, and claims is intended to include both unsubstituted and substituted alkyl groups, the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone, including haloalkyl groups such as trifluoromethyl and 2,2,2-trifluoroethyl, etc.
  • acyl is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)-, preferably alkylC(O)-.
  • acylamino is art-recognized and refers to an amino group substituted with an acyl group and may be represented, for example, by the formula hydrocarbylC(O)NH-.
  • acyloxy is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)O-, preferably alkylC(O)O-.
  • alkoxy refers to an alkyl group having an oxygen attached thereto. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy and the like.
  • alkoxyalkyl refers to an alkyl group substituted with an alkoxy group and may be represented by the general formula alkyl-O-alkyl.
  • C x-y or “C x -C y ”, when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups that contain from x to y carbons in the chain.
  • C 0 alkyl indicates a hydrogen where the group is in a terminal position, a bond if internal.
  • a C 1-6 alkyl group for example, contains from one to six carbon atoms in the chain.
  • alkylamino refers to an amino group substituted with at least one alkyl group.
  • alkylthio refers to a thiol group substituted with an alkyl group and may be represented by the general formula alkylS-.
  • amide refers to a group , wherein R 9 and R 10 each independently represent a hydrogen or hydrocarbyl group, or R 9 and R 10 taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure.
  • amine and “amino” are art-recognized and refer to both unsubstituted and substituted amines and salts thereof, e.g., a moiety that can be represented by , wherein R 9 , R 10 , and R 10 ’ each independently represent a hydrogen or a hydrocarbyl group, or R 9 and R 10 taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure.
  • aminoalkyl refers to an alkyl group substituted with an amino group.
  • aralkyl refers to an alkyl group substituted with an aryl group.
  • aryl as used herein include substituted or unsubstituted single-ring aromatic groups in which each atom of the ring is carbon.
  • the ring is a 5- to 7- membered ring, more preferably a 6-membered ring.
  • aryl also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
  • Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like.
  • carbamate is art-recognized and refers to a group 10 , wherein R 9 and R 10 independently represent hydrogen or a hydrocarbyl group.
  • carbocyclylalkyl refers to an alkyl group substituted with a carbocycle group.
  • carbocycle includes 5-7 membered monocyclic and 8-12 membered bicyclic rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated and aromatic rings.
  • Carbocycle includes bicyclic molecules in which one, two or three or more atoms are shared between the two rings.
  • the term “fused carbocycle” refers to a bicyclic carbocycle in which each of the rings shares two adjacent atoms with the other ring.
  • Each ring of a fused carbocycle may be selected from saturated, unsaturated and aromatic rings.
  • an aromatic ring e.g., phenyl
  • an aromatic ring e.g., phenyl
  • a saturated or unsaturated ring e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits, is included in the definition of carbocyclic.
  • Exemplary “carbocycles” include cyclopentane, cyclohexane, bicyclo[2.2.1]heptane, 1,5-cyclooctadiene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]oct-3-ene, naphthalene and adamantane.
  • Exemplary fused carbocycles include decalin, naphthalene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octane, 4,5,6,7-tetrahydro- 1H-indene and bicyclo[4.1.0]hept-3-ene.
  • Carbocycles may be substituted at any one or more positions capable of bearing a hydrogen atom.
  • the term “carbonate” is art-recognized and refers to a group -OCO 2 -.
  • cycloalkyl includes substituted or unsubstituted non-aromatic single ring structures, preferably 4- to 8-membered rings, more preferably 4- to 6-membered rings.
  • cycloalkyl also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is cycloalkyl and the substituent (e.g., R 100 ) is attached to the cycloalkyl ring, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
  • Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, pyrimidine, denzodioxane, tetrahydroquinoline, and the like.
  • esteer refers to a group -C(O)OR 9 wherein R 9 represents a hydrocarbyl group.
  • ether refers to a hydrocarbyl group linked through an oxygen to another hydrocarbyl group. Accordingly, an ether substituent of a hydrocarbyl group may be hydrocarbyl-O-.
  • Ethers may be either symmetrical or unsymmetrical.
  • ethers include, but are not limited to, heterocycle-O-heterocycle and aryl-O- heterocycle.
  • Ethers include “alkoxyalkyl” groups, which may be represented by the general formula alkyl-O-alkyl.
  • halo and “halogen” as used herein means halogen and includes chloro, fluoro, bromo, and iodo.
  • heteroalkyl and “heteroaralkyl”, as used herein, refers to an alkyl group substituted with a hetaryl group.
  • heteroaryl and “hetaryl” include substituted or unsubstituted aromatic single ring structures, preferably 5- to 7-membered rings, more preferably 5- to 6-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms.
  • heteroaryl and “hetaryl” also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heteroaromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
  • Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like.
  • heteroatom as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur.
  • heterocyclylalkyl refers to an alkyl group substituted with a heterocycle group.
  • heterocyclyl refers to substituted or unsubstituted non-aromatic ring structures, preferably 3- to 10-membered rings, more preferably 3- to 7-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms.
  • heterocyclyl and “heterocyclic” also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heterocyclic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
  • Heterocyclyl groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams, and the like.
  • Hydrocarbyl groups include, but are not limited to aryl, heteroaryl, carbocycle, heterocycle, alkyl, alkenyl, alkynyl, and combinations thereof.
  • hydroxyalkyl refers to an alkyl group substituted with a hydroxy group.
  • lower when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups where there are ten or fewer atoms in the substituent, preferably six or fewer.
  • acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy substituents defined herein are respectively lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy, whether they appear alone or in combination with other substituents, such as in the recitations hydroxyalkyl and aralkyl (in which case, for example, the atoms within the aryl group are not counted when counting the carbon atoms in the alkyl substituent).
  • polycyclyl refers to two or more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls) in which two or more atoms are common to two adjoining rings, e.g., the rings are “fused rings”.
  • Each of the rings of the polycycle can be substituted or unsubstituted.
  • each ring of the polycycle contains from 3 to 10 atoms in the ring, preferably from 5 to 7.
  • sulfate is art-recognized and refers to the group –OSO3H, or a pharmaceutically acceptable salt thereof.
  • sulfonamide is art-recognized and refers to the group represented by the general formulae , wherein R 9 and R 10 independently represents hydrogen or hydrocarbyl.
  • sulfoxide is art-recognized and refers to the group–S(O)-.
  • sulfonate is art-recognized and refers to the group SO3H, or a pharmaceutically acceptable salt thereof.
  • sulfone is art-recognized and refers to the group –S(O) 2 -.
  • substituted refers to moieties having substituents replacing a hydrogen on one or more carbons of the backbone. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds.
  • the permissible substituents can be one or more and the same or different for appropriate organic compounds.
  • the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.
  • Substituents can include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic mo
  • thioalkyl refers to an alkyl group substituted with a thiol group.
  • thioester refers to a group -C(O)SR 9 or –SC(O)R 9 wherein R 9 represents a hydrocarbyl.
  • thioether is equivalent to an ether, wherein the oxygen is replaced with a sulfur.
  • urea is art-recognized and may be represented by the general formula , wherein R 9 and R 10 independently represent hydrogen or a hydrocarbyl.
  • the term “modulate” as used herein includes the inhibition or suppression of a function or activity (such as cell proliferation) as well as the enhancement of a function or activity.
  • pharmaceutically acceptable is art-recognized.
  • the term includes compositions, excipients, adjuvants, polymers and other materials and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • “Pharmaceutically acceptable salt” or “salt” is used herein to refer to an acid addition salt or a basic addition salt which is suitable for or compatible with the treatment of patients.
  • pharmaceutically acceptable acid addition salt means any non-toxic organic or inorganic salt of any base compounds represented by Formula (I), Formula (Ia), or Formula (Ib).
  • Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulfuric and phosphoric acids, as well as metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate.
  • Illustrative organic acids that form suitable salts include mono-, di-, and tricarboxylic acids such as glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, benzoic, phenylacetic, cinnamic and salicylic acids, as well as sulfonic acids such as p- toluene sulfonic and methanesulfonic acids. Either the mono or di-acid salts can be formed, and such salts may exist in either a hydrated, solvated or substantially anhydrous form.
  • mono-, di-, and tricarboxylic acids such as glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, benzoic, phenylacetic, cinnamic and salicylic acids, as well as sul
  • the acid addition salts of compounds of Formula (I), Formula (Ia), or Formula (Ib) are more soluble in water and various hydrophilic organic solvents, and generally demonstrate higher melting points in comparison to their free base forms.
  • the selection of the appropriate salt will be known to one skilled in the art.
  • Other non-pharmaceutically acceptable salts e.g., oxalates, may be used, for example, in the isolation of compounds of Formula (I), Formula (Ia), or Formula (Ib) for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt.
  • pharmaceutically acceptable basic addition salt means any non-toxic organic or inorganic base addition salt of any acid compounds represented by Formula (I), Formula (Ia), or Formula (Ib) or any of their intermediates.
  • Illustrative inorganic bases which form suitable salts include lithium, sodium, potassium, calcium, magnesium, or barium hydroxide.
  • Illustrative organic bases which form suitable salts include aliphatic, alicyclic, or aromatic organic amines such as methylamine, trimethylamine and picoline or ammonia. The selection of the appropriate salt will be known to a person skilled in the art. Many of the compounds useful in the methods and compositions of this disclosure have at least one stereogenic center in their structure.
  • This stereogenic center may be present in a R or a S configuration, said R and S notation is used in correspondence with the rules described in Pure Appl. Chem. (1976), 45, 11-30.
  • the disclosure contemplates all stereoisomeric forms such as enantiomeric and diastereoisomeric forms of the compounds, salts, prodrugs or mixtures thereof (including all possible mixtures of stereoisomers). See, e.g., WO 01/062726.
  • certain compounds which contain alkenyl groups may exist as Z (zusammen) or E (enthafen) isomers. In each instance, the disclosure includes both mixture and separate individual isomers. Some of the compounds may also exist in tautomeric forms.
  • Prodrug or “pharmaceutically acceptable prodrug” refers to a compound that is metabolized, for example hydrolyzed or oxidized, in the host after administration to form the compound of the present disclosure (e.g., compounds of Formula (I), Formula (Ia), or Formula (Ib)).
  • Typical examples of prodrugs include compounds that have biologically labile or cleavable (protecting) groups on a functional moiety of the active compound.
  • Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, or dephosphorylated to produce the active compound.
  • Examples of prodrugs using ester or phosphoramidate as biologically labile or cleavable (protecting) groups are disclosed in U.S. Patents 6,875,751, 7,585,851, and 7,964,580, the disclosures of which are incorporated herein by reference.
  • the prodrugs of this disclosure are metabolized to produce a compound of Formula (I), Formula (Ia), or Formula (Ib).
  • the present disclosure includes within its scope, prodrugs of the compounds described herein. Conventional procedures for the selection and preparation of suitable prodrugs are described, for example, in “Design of Prodrugs” Ed. H. Bundgaard, Elsevier, 1985.
  • pharmaceutically acceptable carrier means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filter, diluent, excipient, solvent or encapsulating material useful for formulating a drug for medicinal or therapeutic use.
  • the term “Log of solubility”, “LogS” or “logS” as used herein is used in the art to quantify the aqueous solubility of a compound. The aqueous solubility of a compound significantly affects its absorption and distribution characteristics.
  • Purified compounds were further dried under high vacuum or in a desiccator. Yields correspond to purified compounds, and were not further optimized.
  • Proton nuclear magnetic resonance ( 1 H NMR) spectra were recorded on Bruker spectrometers (operating at 300, 400, or 500 MHz).
  • Carbon NMR ( 13 C NMR) spectra were recorded on Bruker spectrometers (either at 400 or 500 MHz).
  • NMR chemical shifts ( ⁇ ppm) were referenced to the residual solvent signals.
  • JGK071 N-(3-Bromo-2-fluorophenyl)-10-fluoro-7,8-dihydro[1,4]dioxino[2,3-g]quinazolin-4-amine.
  • compound JGK071 was prepared from chloroquinazoline 17 (35 mg, 0.15 mmol) and 3-bromo-2-fluoroaniline.
  • FC DCM/EtOAc 1:0 ⁇ 8:2 afforded JGK071 (44 mg, 77%) as a white solid.
  • the resulting mixture was heated to 90 °C and allowed to stir overnight, after which it was cooled to room temperature, water was added, and the resulting mixture was extracted with ethyl acetate (EtOAc). The combined organic phases were dried over Na2SO4, the mixture was filtered, the filtrate was concentrated. The resulting product was purified by reverse-phase HPLC (RP-HPLC), and the active fractions were combined and concentrated to provide a product that was further extracted with a saturated solution of NaHCO3 and EtOAc. The combined organic fractions were washed with brine, dried over Na2SO4, filtered, and concentrated to give the title compound (47 mg, 21%).
  • RP-HPLC reverse-phase HPLC
  • the PC-9 cell line was purchased from Sigma, and the HCC827 cell line was purchased from ATCC. Each cell line was maintained at ⁇ passage 10 at 37 o C in a humidified incubator with 5%CO 2 . Cells were plated in 96-well optical bottom plates (Corning #3903; Corning, NY) at a cell density of 5,000 cells/well, allowed to adhere for minimally 16 hours, and subsequently treated with the test compounds using an 11-point serial dilution (1:3) in duplicate using an HP D300 digital 4 dispenser (Tecan, Morrisville, NC).

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Abstract

La présente invention concerne des composés qui sont capables de traverser la barrière hémato-encéphalique pour moduler l'activité de la tyrosine kinase EGFR. L'invention concerne également des méthodes de traitement du glioblastome et d'autres cancers médiés par EGFR. L'invention concerne aussi des méthodes de traitement du glioblastome et d'autres cancers médiés par EGFR dont il a été déterminé qu'ils présentent un métabolisme du glucose modifié en présence d'inhibiteurs. La présente invention concerne également des procédés d'administration à un sujet d'un inhibiteur du métabolisme du glucose et d'un stabilisateur de p53 cytoplasmique.
PCT/US2021/051024 2020-09-21 2021-09-20 Compositions et méthodes pour traiter le cancer WO2022061202A1 (fr)

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